The objective of this proposal is to study the mechanisms involved in the pathophysiology of major depression (MDD) in patients with type 2 diabetes mellitus. Our preliminary findings indicate that MDD in patients with type 2 diabetes is associated with specific changes in brain physiology, anatomy and behavior. In this application, we propose to expand on those observations and examine the biophysical status of proteins and glial functions in cortical and subcortical regions using in vivo neuroimaging approaches. Magnetization transfer (MT) and 2 dimensional magnetic resonance spectroscopy (2D MRS) will be used to estimate MT Ratios (a measure of protein status in the gray and white matter) and levels of glutamate and aspartate in frontal and subcortical regions respectively. These include the anterior cingulate cortex, and the dorsolateral white matter regions and subcortical nuclei bilaterally. We will also study the relationship of MT ratios to specific cognitive domains including attention, executive functions, learning and memory and psychomotor processing. Three comparison groups: non-depressed diabetic controls, healthy non-depressed non-diabetic subjects and patients with unipolar depression without diabetes, will be examined in order to determine the specificity of our findings and the nature and magnitude of the changes across study groups. Collectively, these findings will provide important insights into the neurobiological basis of mood disorders and their relationship to cortical and subcortical circuits and cognition. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a common medical disorder that is responsible for considerable morbidity and mortality. Mood disturbances are common in diabetes and yet there is little understanding of its pathophysiological underpinnings. The proposed study will utilize magnetic resonance imaging (MRI) based cutting edge approaches and neuropsychological testing to study the neuronal circuits (brain regions and connections) that mediate depression in this clinical population.